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Animal models (e.g. rats, mice, monkeys, pigs, dogs) have been used by researchers in biological research and are a common point of debate in our society. The anatomical and physiological similarities between humans and these animals and the possibility of genetic engineering have allowed researchers to understand biological mechanisms and assess novel therapies in animal models prior to application in humans [1]. However, due to obvious differences between humans and animals, not all results obtained from animal studies are completely representative of human responses. Many novel drugs go through animal testing before entering clinical trials, and the majority of them fail in the clinic. Further contributing to the debate would be the right of animal usage for human benefits and the infliction of harm to the animals [2].

For a long time, there were no in vitro platforms or alternatives available that were capable of mimicking in vivo responses seen in animal models. However, recently, organ-on-chip (OoC) systems have become available as an alternative to animal models.

OoC systems

OoC platforms are where biology is coupled with microtechnology, a relatively new addition to available model biological systems for researchers to investigate aspects of human physiology underlying health and disease [3]. The chip is in the form of a microfluidic device that contains networks of fine microchannels that allow minute volumes of solutions (from picolitres to millilitres) to be guided and manipulated. For example, this allows the delivery of cell culture media and the removal of metabolites and cellular waste or debris. Real-time sensors, such as microelectrodes, can also be incorporated to allow monitoring of cell health and response to various treatment conditions.

In this microfluidic chip, miniature versions of tissues are grown and the conditions are maintained at a semblance of the in vivo biochemical and physical environment, allowing them to mimic physiological tissue-specific functions.

All OoC systems have three main defining characteristics [4]. The first characteristic is the 3D arrangement of the tissues, capable of including multiple layers of cells such as those seen in stratified squamous epithelium structures. Secondly, the presence of multiple cell types to reflect the physiological cell balance. For example, inclusion of stromal, vascular, parenchymal, and immune cells. The third characteristic is the presence of biomechanical forces present in the modelled tissue, such as hemodynamic shear forces in vascular tissues and stretch forces in lung tissues. These characteristics allow maximal imitation of the physiological state and environments found in the human body.

Figure 1. An example of an Organ-on-chip and how it works [5]

The first ‘lung-on-a-chip’

The first research published on ‘lung-on-a-chip’ set the stage for OoCs. In 2010, Huh et al. [6] designed a microsystem that consists of epithelial cells and endothelial cells, together with extracellular matrix, that models the alveolar-capillary interface of the human lung. The microdevice reproduces complex integrated organ-level functions and responses to various conditions, such as pathogen-induced inflammatory responses and cytokine exposure.

Studies on the effect of silica nanoparticles have been carried out on this lung model. Results showed that mechanical strain on the lung structures enhances toxic and inflammatory responses of the lung to these silica nanoparticles. The mechanical strain was also found to increase both epithelial and endothelial uptake of nanoparticle materials and induce their transport into the underlying microvascular channel. Observations on whole mouse lung showed similar results of nanoparticle absorption, thus showing the ability of the microdevice to mimic in vivo lung conditions.

Other examples of organ-on-chips

Besides from the lung, other organs have also been developed on this microdevice technology. For example, heart-on-chip houses cardiomyocytes (heart muscle cells), which are elongated and lined up next to each other [7]. A dog-bone shaped chamber was used, allowing the cardiomyocytes to align themselves comfortably. Proper arrangement of these cells can form a real muscle fibre and reach the maximum power for each heartbeat. Fat-on-chip is also available as a model for adipose tissues, containing adipocytes in a cylindrical chamber [8]. This allows the research of adipose tissue biology and obesity-related conditions without needing induced-obesity in animal models.

Figure 2. Examples of Heart- and Fat-on-chip [5]

Organs in our body are dependent on each other to function properly, with constant communication using messenger molecules that travel through the bloodstream. Therefore, multi-organ-chips can be formed by linking two organ-on-chip bricks using a connector brick, forming a common blood channel that allows cross-talks between the organs. Multiple types and number of organs can be linked through this method, allowing comprehensive analysis of the effects of various conditions or treatments on the biological system [9].

Figure 3. Building a multi-organ-chip [5]


The applicability of this organ-on-chip system for investigation of physiological functions and drug testing has been demonstrated by various studies. The increasingly predictive capabilities of the system for integrated human physiology puts OoC technology on track to becoming a common human-specific experimental in vitro platform for applications in preclinical research and testing of novel therapeutics [3].

Formation of a new institute in the National Institutes of Health (US) that focuses on in vitro models has been proposed [10]. This may aid in increasing familiarity with these technologies and engage a critical mass of researchers to use this technology, hence encouraging more people to start looking beyond animal models.


[1] Phillips, N.L.H. and Roth, T.L. (2019) ‘Animal models and their contribution to our understanding of the relationship between environments, epigenetic modifications, and behavior’, Genes, 10(1), p.47. [Online] DOI: 10.3390/genes10010047

[2] Barré-Sinoussi, F. and Montagutelli, X. (2015) ‘Animal models are essential to biological research: issues and perspectives’, Future science OA, 1(4). [Online] DOI: 10.4155/fso.15.63

[3] Leung, C.M., De Haan, P., Ronaldson-Bouchard, K., Kim, G.A., Ko, J., Rho, H.S., Chen, Z., Habibovic, P., Jeon, N.L., Takayama, S. and Shuler, M.L. (2022) ‘A guide to the organ-on-a-chip’, Nature Reviews Methods Primers, 2(1), p.33. [Online] DOI: 10.1038/s43586-022-00118-6

[4] Low, L.A., Mummery, C., Berridge, B.R., Austin, C.P. and Tagle, D.A. (2021) ‘Organs-on-chips: into the next decade’, Nature Reviews Drug Discovery, 20(5), pp.345-361. [Online] DOI: 10.1038/s41573-020-0079-3

[5] Rogal, J., Cipriano, M. and Loskill, P. (2020) ‘Organ-on-chip: Playing Lego® with mini-organs to reduce animal testing and make medicines safer’, Frontiers, 8(544390). [Online] DOI: 10.3389/frym.2020.544390

[6] Huh, D., Matthews, B.D., Mammoto, A., Montoya-Zavala, M., Hsin, H.Y. and Ingber, D.E. (2010) ‘Reconstituting organ-level lung functions on a chip’, Science, 328(5986), pp.1662-1668. [Online] DOI: 10.1126/science.1188302

[7] Schneider, O., Zeifang, L., Fuchs, S., Sailer, C. and Loskill, P. (2019) ‘User-friendly and parallelized generation of human induced pluripotent stem cell-derived microtissues in a centrifugal heart-on-a-chip’, Tissue Engineering Part A, 25(9-10), pp.786-798. [Online] DOI: 10.1089/ten.tea.2019.0002

[8] Rogal, J., Binder, C., Kromidas, E., Roosz, J., Probst, C., Schneider, S., Schenke-Layland, K. and Loskill, P. (2020) ‘WAT-on-a-chip integrating human mature white adipocytes for mechanistic research and pharmaceutical applications’, Scientific Reports, 10(1), pp.1-12. [Online] DOI: 10.1038/s41598-020-63710-4

[9] Loskill, P., Marcus, S.G., Mathur, A., Reese, W.M. and Healy, K.E. (2015) ‘μOrgano: A Lego®-like plug & play system for modular multi-organ-chips’, PLoS One, 10(10), p.e0139587. [Online] DOI: 10.1371/journal.pone.0139587

[10] Horejs, C. (2021) ‘Organ chips, organoids and the animal testing conundrum’, Nature Reviews Materials, 6(5), pp.372-373. [Online] DOI: 10.1038/s41578-021-00313-z


This article was prepared by Phoebe Tee


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